Faculty Profiles - KAGAWA Shunsuke

Randomized Controlled Trial of Epidural versus Patient-controlled Intravenous Analgesia for Postoperative Pain Control after Laparoscopic Gastrectomy. Reviewed

Kikuchi S, Kuroda S, Nishizaki M, Matsusaki T, Mitsuhashi T, Kuwada K, Kagawa S, Morimatsu H, Fujiwara T

Acta medica Okayama 72 ( 1 ) 95 - 98 2018.2

Language：English Publishing type：Research paper (scientific journal)

Although epidural analgesia (EDA) is considered standard postoperative analgesia for open gastrectomy, it has been unclear whether EDA has benefits in laparoscopic gastrectomy (LG) because postoperative pain after a laparoscopic procedure is significantly reduced. We are conducting a two-arm, single-center, prospective randomized non-inferiority trial to evaluate the postoperative pain relief of patient-controlled intravenous analgesia (PCIA) compared to EDA. A total of 132 patients undergoing LG will be randomized to EDA and PCIA groups (n=64 each) for postoperative pain control. The primary endpoint is postoperative pain at 24 h after surgery. This study will clarify the optimal pain management after LG.

DOI： 10.18926/AMO/55671

Iron depletion is a novel therapeutic strategy to target cancer stem cells. International journal

Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

Oncotarget 8 ( 58 ) 98405 - 98416 2017.11

Language：English Publishing type：Research paper (scientific journal)

Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

DOI： 10.18632/oncotarget.21846

[Radical Thoracoscopic Esophagectomy for Elderly Patients with Advanced Esophageal Cancer].

Yuki Matsumi, Yasuhiro Shirakawa, Shunsuke Tanabe, Satoshi Komoto, Naoaki Maeda, Takayuki Ninomiya, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 12 ) 1784 - 1786 2017.11

Language：Japanese Publishing type：Research paper (scientific journal)

We report a case of an elderly patient with advanced esophageal cancer who underwent multidisciplinary treatment. An 86-year-old male consulted our hospital with complaints of pharynx discomfort and difficulty in swallowing. He was preoperatively diagnosed with esophageal cancer, T3N2M0, Stage III . We performed 2 courses of cisplatin plus 5-FU therapy as neoadjuvant chemotherapy. The primary tumor and metastatic lymph nodes reduced in size, and thoracoscopic esophagectomy in the prone position was performed. Pathological findings were esophageal cancer, pT3-Ad, INF b, ly2, v1, IM0, pPM0, pDM0, pRM1, pN3, pStage III . As the radical margin was positive, chemoradiotherapy was performed. We continued postoperative chemotherapy for approximately 1 year, and the patient has survived without relapse for 4 years from esophagectomy. Even in patients over 80 years old, long-term prognosis can be expected by performing radical surgery and chemoradiotherapy.

Novel therapeutic strategy for human epidermal growth factor receptor 2-positive gastric cancer

Nobuhiko Kanaya, Shinji Kuroda, Tetsushi Kubota, Toshiaki Morihiro, Satoru Kikuchi, Masahiko Nishizaki, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

Japanese Journal of Cancer and Chemotherapy 44 ( 10 ) 883 - 885 2017.10

Language：Japanese Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.

Trastuzumab (Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2 (HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanopartides, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanopartides and demonstrate their efficacy for the treatment of HER2-positive, Tmab-resistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanopartides have the potential to be a novel HER2-targeted therapeutic agent.

Scopus

Clinicopathological features of gastric cancer in young patients; Multicenter retrospective study

Yoshiyasu Kono, Hiromitsu Kanzaki, Masahiro Takatani, Junichirou Nasu, Ryuta Takenaka, Hiroyuki Sakae, Ko Miura, Takehiro Tanaka, Shunsuke Kagawa, Hiroyuki Okada

ANNALS OF ONCOLOGY 28 2017.10

Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system

Katsuyuki Aoyama, Shinji Kuroda, Toshiaki Morihiro, Nobuhiko Kanaya, Tetsushi Kubota, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

SCIENTIFIC REPORTS 7 ( 14177 ) doi: 10.1038/s41598-017-14717-x 2017.10

Language：English Publishing type：Research paper (scientific journal) Publisher：NATURE PUBLISHING GROUP

Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

DOI： 10.1038/s41598-017-14717-x

若き外科医からの提言わたしたちの将来の外科医療を見据えて外科研修の現状からみえた若手外科医の求めるもの大規模Surveyより

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction. Reviewed

Yamakawa Y, Tazawa H, Hasei J, Osaki S, Omori T, Sugiu K, Komatsubara T, Uotani K, Fujiwara T, Yoshida A, Kunisada T, Urata Y, Kagawa S, Ozaki T, Fujiwara T

Cancer science 108 ( 9 ) 1870 - 1880 2017.9

菊地覚次, 野間和広, 山根正修, 岸本浩行, 黒田新士, 香川俊輔, 新井禎彦, 佐野俊二, 三好新一郎, 藤原俊義

日本外科学会雑誌 118 ( 5 ) 588 - 590 2017.9

Training system for laparoscopy-assisted distal gastrectomy

Shinji Kuroda, Satoru Kikuchi, Naoto Hori, Shuichi Sakamoto, Tetsuya Kagawa, Megumi Watanabe, Tetsushi Kubota, Kazuya Kuwada, Michihiro Ishida, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

SURGERY TODAY 47 ( 7 ) 802 - 809 2017.7

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Purpose Laparoscopy-assisted distal gastrectomy (LADG) is likely to become a standard procedure for gastric cancer, which highlights the importance of establishing a training system in which even inexperienced surgeons can perform this procedure safely. This study assesses our training system for LADG based on short-term surgical outcomes.
Methods We evaluated retrospectively the short-term outcomes of 100 consecutive LADGs with curative D1/D1+ lymph node dissection. Our training system was assessed based on the learning curve of trainees, and factors related to achieving good-quality operations were analyzed statistically.
Results Overall, postoperative complications developed in 10 patients (10%), and included one case of anastomotic leakage (1%) and one case of pancreatic fistula (1%). The learning curve of the trainees plateaued after 10 operator cases in terms of operation time. The importance of the trainer's position was also confirmed by the result that the operation time was significantly longer when trainees with <= 10 operator cases performed LADG with a trainer as scopist vs. a trainer as the first assistant. Univariate and multivariate analyses revealed that > 10 operator cases were the most important factor for achieving good-quality operations.
Conclusion These results show that our current LADG procedure and training system are appropriate and effective.

DOI： 10.1007/s00595-016-1439-9

Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer

Hiroshi Tazawa, Shinji Kuroda, Joe Hasei, Shunsuke Kagawa, Toshiyoshi Fujiwara

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 18 ( 7 ) doi:10.3390/ijms18071479 2017.7

Language：English Publisher：MDPI AG

Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a cytoprotective process that produces energy via lysosomal degradation of intracellular components as a physiologic response to various stresses, including hypoxia, nutrient deprivation, and disruption of growth signaling. However, infection with oncolytic adenoviruses induces autophagy and subsequent death of tumor cells rather than enhancing their survival. In this review, we summarize the beneficial role of autophagy in oncolytic adenoviral therapy, including the roles of infection, replication, and cell lysis. Numerous factors are involved in the promotion and inhibition of oncolytic adenovirus-mediated autophagy. Furthermore, recent evidence has shown that oncolytic adenoviruses induce autophagy-related immunogenic cell death (ICD), which enhances the antitumor immune response by inducing the activation of danger signal molecules and thus represents a novel cancer immunotherapy. Understanding the precise role of oncolytic adenovirus-induced autophagy and ICD could enhance the therapeutic potential of oncolytic adenoviral therapy for treating various cancers.

DOI： 10.3390/ijms18071479

GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D GelfoamA (R) histoculture

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 6 ) 479 - 482 2017.7

Management of early gastric cancer that meet the indication for radical lymph node dissection following endoscopic resection: a retrospective cohort analysis

Satoru Kikuchi, Shinji Kuroda, Masahiko Nishizaki, Tetsuya Kagawa, Hiromitsu Kanzaki, Yoshiro Kawahara, Shunsuke Kagawa, Takehiro Tanaka, Hiroyuki Okada, Toshiyoshi Fujiwara

BMC SURGERY 17 ( 1 ) 687 - 694 2017.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Endoscopic resection (ER) has been widely accepted as the standard treatment for early gastric cancer (EGC). However, in patients considered to have undergone non-curative ER due to their potential risk of lymph node metastasis (LNM), additional gastrectomy is recommended. The aim of the present study was to identify EGC patients after non-curative ER at high risk of LNM.
Methods: A total of 150 patients who had undergone ER for EGC were diagnosed as non-curative ER due to their potential risk of LNM. Clinicopathological data and clinical outcomes were examined retrospectively.
Results: Additional gastrectomy with lymph node dissection was performed in 73 patients, and the remaining 77 patients were followed-up without additional gastrectomy. In patients who underwent additional gastrectomy, 8 patients had local residual tumor, and 8 patients had LNM, which were limited in the peritumoral nodes. Only lymphatic invasion (p = 0.012) was a statistically significant factor for LNM. The 5-year overall survival and recurrence-free survival were not significantly different between patients with and without additional gastrectomy.
Conclusion: Additional gastrectomy with lymph node dissection is recommended for patients who were diagnosed as non-curative ER with lymphatic invasion, and minimizing the extent of lymph node dissection may be allowed for these patients.

DOI： 10.1186/s12893-017-0268-0

Nonexposure laparoscopic and endoscopic cooperative surgery (closed laparoscopic and endoscopic cooperative surgery) for gastric submucosal tumor

Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Tanabe, Kazuhiro Noma, Shunsuke Kagawa, Yasuhiro Shirakawa, Hiroshi Kato, Hiroyuki Okada, Toshiyoshi Fujiwara

GASTRIC CANCER 20 ( 3 ) 553 - 557 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：SPRINGER

Laparoscopic and endoscopic cooperative surgery (LECS) is increasingly applied for gastric submucosal tumors (SMTs) such as gastrointestinal stromal tumors. However, the conventional LECS procedure has the potential risk that gastric contents and even tumor cells could spread into the abdominal cavity because the gastric wall has to be opened during the resection. To avoid this problem, we have developed a modified LECS procedure named "closed LECS." Ten patients underwent closed LECS for the resection of gastric SMTs. Closed LECS consists of the following steps: endoscopic submucosal layer dissection around the tumor, laparoscopic marking of a resection line on the serosal surface along submucosal dissection line, seromuscular suturing with the marked lesion inverted into the inside of the stomach, endoscopic circumferential seromuscular dissection, and peroral retrieval. In three of the initial five cases, the closed LECS procedure was not completed as planned because of the tumor size and endoscopic inappropriate seromuscular dissection. After modification of the procedure, the entire procedure was successful in all five cases. The mean resected tumor diameter was 24.1 +/- 7.6 mm. The mean operation time was 253 +/- 45 min. One patient experienced an intra-abdominal abscess potentially related to delayed perforation as a postoperative complication. The closed LECS procedure for gastric SMTs can theoretically be applied without contamination and tumor cell dissemination into the abdominal cavity.

DOI： 10.1007/s10120-016-0641-1

Outcome of Radiation Monotherapy for High-risk Patients with Stage I Esophageal Cancer

Yasuhiro Shirakawa, Kazuhiro Noma, Naoaki Maeda, Shunsuke Tanabe, Shinji Kuroda, Shunsuke Kagawa, Kuniaki Katsui, Norihisa Katayama, Susumu Kanazawa, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 71 ( 2 ) 127 - 133 2017.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

Currently, chemoradiation is the most widely used nonsurgical treatment for esophageal cancer. However, some patients, particularly the very elderly or those with severe vital organ dysfunction, face difficulty with the chemotherapy component. We therefore examined the outcome of radiation therapy (RT) alone for patients with esophageal cancer at our facility. Between January 2005 and December 2014, 84 patients underwent RT at our hospital, and 78 of these patients received concomitant chemotherapy. The remaining 6 patients underwent RT alone; these patients were considered to be high-risk and to have no lymph node metastasis (stage I). Five of them received irradiation up to a curative dose: 4 showed a complete response (CR) and 1 showed a partial response (PR). Of the patients exhibiting CR, 3 are currently living recurrence-free, whereas 1 patient underwent endoscopic submucosal dissection (ESD) as salvage therapy for local recurrence, with no subsequent recurrence. High-risk stage I esophageal cancer patients can be treated radically with RT alone under certain conditions. In the future, to broaden the indications for RT monotherapy to include some degree of advanced cancers, a novel concurrent therapy should be identified.

High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 4 ) 285 - 287 2017.4

[Multiple Salvage Radiotherapies for Metachronous Lymph Node Metastasis from Gastric Cancer Contributed to Long-Term Management of Disease].

Naoto Hori, Shunsuke Kagawa, Satoru Kikuchi, Shinji Kuroda, Megumi Watanabe, Shuichi Sakamoto, Tetsuya Kagawa, Kazuya Kuwada, Tetsushi Kubota, Hiroyuki Kishimoto, Masahiko Nishizaki, Norihisa Katayama, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 44 ( 2 ) 165 - 167 2017.2

Language：Japanese Publishing type：Research paper (scientific journal)

A 70-year-old man who underwent gastrectomy for Stage III C gastric cancer developed lymph node(LN)metastasis posterior to the pancreatic head 3 years after the radical surgery.He was first treated with radiotherapy(RT)followed by chemotherapy.The irradiated tumor regressed completely.However, the cancer relapsed in a single para-aortic LN and he was treated with RT to the lesion followed by chemotherapy.Although it completely regressed, later, lung metastasis was observed.The lung lesions were well suppressed by switching to docetaxel; however, the cancer relapsed again in a mediastinal LN, and it was not responsive to docetaxel.The growing mediastinal lesion was irradiated again, which resulted in stable disease.The patient has been treated for 4 years and 7 months with all lesions being well-managed, and chemotherapy is being continued.Recurrent gastric cancer after surgery tends to present as multiple lesions; therefore, the principle therapy is systemic chemotherapy and RT is unlikely to be suitable.However, especially in cases of a solitary lesion that is chemo-resistant, RT could be an optimal option and contribute to long-term survival even in patients with recurrent gastric cancer.

Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging

Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL 53 ( 2 ) 96 - 98 2017.2

Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models. International journal

Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M Hoffman

Anticancer research 37 ( 1 ) 57 - 60 2017.1

Language：English Publishing type：Research paper (scientific journal)

BACKGROUND: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. MATERIALS AND METHODS: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. RESULTS: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDA-MB-231 tumors were resected. CONCLUSION: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.